Three isoforms of the alpha ("catalytic") subunit of Na+, K+-ATPase, derived from distinct genes, have been identified in the central nervous system by others. While these findings suggest that brain homeostasis is dependent on multiple functions of Na+, K+-ATPase, the inability to distinguish the activities of all three isoforms, in a crude preparation, has precluded a precise examination of this hypothesis. As demonstrated by others, we have distinguished two components of ouabain-inhibitable K+ uptake into crude nerve-ending (synaptosome) preparations at physiological levels of K+ (5 Mm). Specifically, Na+, K+- ATPase activities which were sensitive (S; IC50=10-6 squared M) and relatively insensitive (I; IC50= 10-4 squared M) to ouabain could be defined under three conditions. Recently, we have demonstrated that reduction of K+ promotes the binding of low concentrations of ouabain and facilitates the distinction of a third Na+, K+-ATPase activity which is very sensitive (VS; IC50 less than 1007 M) to ouabain. Differential function of all three Na+, K+-ATPase isoform activities have been defined based on differences in brain region localization and in responses to K+ and neurotransmitters. Under physiological conditions, VS is apparently an inducible pool of Na+, K+-ATPase has been found to be selectively activated by Noradrenaline (EC50= 10-9 squared M) and pharmacological ethanol (EC50 = 3.3 Mm). Present work involves 1) the further characterization of the function and regulation of Na+, K+-ATPase isoform activities, 2) the potential role of Na+, K+-ATPase in alcoholism and other behavioral disorders, 3) the identification of the genetic basis (isozyme) for the activities of VS, S and I and 4) the characterization of endogenous "ouabain-like" regulators of Na+, K+-ATPase activity.